Despite her early success, she took a sabbatical from 1999 to 2004. She returned for one of her best known roles to date, the character Deb in the 2004 film Napoleon Dynamite. Since her return to acting, Majorino has been in television series such as Veronica Mars, Big Love, True Blood and Grey's Anatomy. Majorino returned to the role of Mac in the Veronica Mars movie, and has played the part of Maggie Harris on TNT's Legends TV series.

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Majorino was born in Westlake, California, the daughter of Sarah (née Black) and real estate agent Robert "Bob" Majorino.[3] Her father is of Italian, Cuban, and French descent, and her mother has English and German ancestry.[4][5] She has an older brother, Kevin, with whom she has formed a rock band, The AM Project.[6]

She played the title role in the 1999 television film, Alice in Wonderland. After Alice, Majorino took time off from the business. She has since cited burnout as the reason for her hiatus from acting. Majorino did not appear in another film until the 2004 cult filmNapoleon Dynamite.[10] From 2004 onward, she played a recurring role on UPN's series, Veronica Mars, as the computer-savvy Cindy "Mac" Mackenzie. This role began in the show's eighth episode, "Like a Virgin", and continued until the show's series finale, "The Bitch is Back". Show creator Rob Thomas created the role with her in mind. Majorino had met Thomas while interviewing him for a report on one of his books.[8] Majorino became a series regular in the show's third and final season.[11] During her time on Veronica Mars, she also started appearing in a recurring role on the cable television series Big Love with Waterworld costar Jeanne Tripplehorn and fellow Veronica Mars cast members Amanda Seyfried and Kyle Gallner.[10] In 2005, she appeared in the music video for the song "Blind" by rock group Lifehouse.[12][13]

She started filming for The Deep End, a television show for ABC in 2009. She played the role of Addy Fisher, a meek and insecure first-year associate at a high profile law firm.[14][15][16] The show was canceled after only six episodes were aired.[17]

She returned to television in 2011 playing the recurring role of Special Agent Genny Shaw on Bones. She also starred in the music video for "Fuckin' Perfect" by Pink.

In 2012, she reprised her role as Deb in the animated TV version of Napoleon Dynamite. She was also seen playing the role of the vampire Molly in Season 5 of the HBO television series True Blood, an uncredited role as a pregnant woman in the Fox show, Raising Hope, in an episode titled "Tarot Cards," and the role of intern Dr. Heather Brooks in Season 9 of the ABC series Grey's Anatomy, with her character being killed off in the two-part premiere of Season 10. In 2014 she appeared in the Veronica Mars film as her character Mac, a project financed by fans through Kickstarter.[18]